This application for a Mentored Patient-oriented Career Development Award (K23) is to support the development of the candidate into a independent investigator capable of conducting large scale clinical trials in psychiatry that address issues of treatment efficacy and effectiveness in addition to serving as the clinical basis for pharmacogenetic studies. The development plan has four major goals: 1) Gain expertise in the design of a clinical trial in schizophrenia, 2) Participate in the execution of a clinical trial, 3) Utilize statistical methodology to analyze clinical trials studies, and 4) Conduct pharmacogenetic analyses of clinical trials data. To accomplish these aims, three major career development activities are proposed: 1) A didactic program to prepare the candidate to independently design, conduct, and analyze clinical trials, 2) Participation in a large clinical trial comparing new antipsychotic medications in patients experiencing their first episode of schizophrenia. This will involve the candidate's participation in the clinical trial as an investigator and will provide the opportunity to develop a pharmacogenetic protocol and, 3) The design, conduct and analysis of a pilot study of the effects of adding the serotonin re-uptake inhibitor, sertraline, to the antipsychotic treatment regimen of schizophrenia patients with treatment-refractory hallucinations. The research plan incorporates two studies. The first is a pharmacogenetic assessment of response to the antipsychotic agents olanzapine and risperidone. This study involves determination of genotype at specific candidate loci within the dopamine and Serotonin receptor systems and case-control and family-based association analysis between these loci and clinical phenotypes of treatment response, drug-induced weight gain and drug-induced extra pyramidal symptoms. The second study is a clinical trial examining sertraline augmentation in schizophrenia patients with hallucinations. The basis of this study is evidence from clinical trials research as well as molecular genetics. This represents an initial effort to utilize the two distinct methodologies to enhance the treatment of schizophrenia. The career development activities and completion of the research studies described in this application are expected to provide the candidate with the knowledge and research experience to develop into an independent investigator with the expertise to conduct high quality clinical trials that incorporate pharmacogenetics into psychiatry.